Modulating Hsf1 Levels Impacts Expression Of The Estrogen Receptor Alpha And Antiestrogen Response

Master transcription factors control the transcriptional program and are essential to maintain cellular functions. Among them, steroid nuclear receptors, such as the estrogen receptor alpha (ER alpha), are central to the etiology of hormone-dependent cancers which are accordingly treated with corresponding endocrine therapies. However, resistance invariably arises. Here, we show that high levels of the stress response master regulator, the heat shock factor 1 (HSF1), are associated with antiestrogen resistance in breast cancer cells. Indeed, overexpression of HSF1 leads to ER alpha degradation, decreased expression of ER alpha-activated genes, and antiestrogen resistance. Furthermore, we demonstrate that reducing HSF1 levels reinstates expression of the ER alpha and restores response to antiestrogens. Last, our results establish a proof of concept that inhibition of HSF1, in combination with antiestro-gens, is a valid strategy to tackle resistant breast cancers. Taken together, we are proposing a mechanism where high HSF1 levels interfere with the ER alpha-dependent transcriptional program leading to endocrine resistance in breast cancer.